A TNF- and c-Cbl-dependent FLIPS-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis

Manikuntala Kundu, Sushil Kumar Pathak, Kuldeep Kumawat, Sanchita Basu, Gargi Chatterjee, Shresh Pathak, Takuya Noguchi, Kohsuke Takeda, Hidenori Ichijo, Christine B.F. Thien, Wallace Y. Langdon, Joyoti Basu

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)


Apoptosis is central to the interaction between pathogenic mycobacteria and host macrophages. Caspase-8-dependent apoptosis of infected macrophages, which requires activation of the mitogen-activated protein (MAP) kinase p38, lowers the spread of mycobacteria. Here we establish a link between the release of tumor necrosis factor (TNF) and mycobacteria-mediated macrophage apoptosis. TNF activated a pathway involving the kinases ASK1, p38 and c-Abl. This pathway led to phosphorylation of FLIPS, which facilitated its interaction with the E3 ubiquitin ligase c-Cbl. This interaction triggered proteasomal degradation of FLIPS, which promoted activation of caspase-8 and apoptosis. Our findings identify a previously unappreciated signaling pathway needed for Mycobacterium tuberculosis-triggered macrophage cell death.

Original languageEnglish
Pages (from-to)918-926
Number of pages9
JournalNature Immunology
Issue number8
Publication statusPublished - 2009
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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